Radiation therapy is utilized to treat approximately 50% of all patients with cancer. However, a fundamental gap in improving the efficacy of radiation therapy exists because the mechanisms by which radiotherapy controls tumors remain poorly understood. For example, although hypoxia is a well-established cause of resistance to radiation therapy, the signal transduction pathways by which hypoxia regulates tumor response to radiation therapy remains to be fully elucidated. The overall goal of this research is to better understand how the efficacy of radiation therapy is influenced by the tumor stroma and microenvironment. We hypothesize that radiation therapy cures cancer by killing tumor parenchymal cells, but the tumor stroma influences the response of tumor parenchymal cells to radiation by regulating the tumor microenvironment. To study the complex interactions of tumor stroma and parenchymal cells during radiation therapy, we have generated novel genetically engineered mice. Previously, we used Cre recombinase to develop genetically engineered mouse models of soft tissue sarcoma to study radiation biology. We have now generated novel strains of genetically engineered mice in which primary cancers can be generated with Flp recombinase. In this system, Cre recombinase can still be utilized to modify genes specifically in the tumor stroma. Utilizing Flp and Cre recombinases (i.e. dual recombinase technology) to study the tumor microenvironment's impact on radiation therapy is highly innovative because primary cancers can be initiated with one recombinase, while the other recombinase can be utilized to specifically modify tumor stromal cells. The proposed research is significant, because we will dissect the mechanisms by which myeloid cells are recruited to tumors during radiation therapy to regulate tumor response. Ultimately, such knowledge has the potential to lay the foundation for novel approaches to improve the efficacy of radiation therapy.